Vision impairment due to glaucoma affects millions of people worldwide with hundreds of thousands of new cases of glaucoma diagnosed in the United States each year. In open angle glaucoma, the most frequent form of the disease, visual field loss is caused by progressive optic nerve fiber loss concomitant with elevated intraocular pressure (IOP). High IOP due to aqueous humor buildup is a major risk factor of glaucoma, and is thought to induce chronic and progressive death of retinal ganglion cells (RGCs). It is estimated that RGCs die by apoptosis at a constant rate of approximately 4% per week during continuous exposure to ocular hypertension, leading to nerve damage. Although treatments are often successful at normalizing high IOP, progressive RGC death and visual field loss generally continue.
Lack of trophic support by a family of growth factors known as neurotrophins (NTFs) has been suggested as a factor in RGC death in glaucoma. NTFs regulate neuronal development, growth, survival, differentiation, maintenance of neuronal cell phenotype and function. The NTFs include Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3) and Neurotrophin-4 (NT-4) and these NTFs bind to two transmembrane receptors, the high affinity receptor family tyrosine kinase (Trk) (TrkA, Trk B and Trk C) (Kd=10-100 pM) and the p75 receptor (Kd=1 nM). Although Trk family receptor ligands are quite selective (e.g., NGF binds TrkA, BDNF binds TrkB; and NT-3 binds mainly TrkC), the p75 receptor is bound non-selectively by all NTFs, making its activation quite promiscuous. The two receptors are believed to have opposing actions, with Trk family receptors mediating signal transduction associated with “positive” signals of cell survival and differentiation, maintenance and repair. The p75 receptor is thought to regulate ligand affinity for Trk receptors and, consequently, ligand-dependent Trk activation and concomitant tyrosine kinase activity, in addition to its own pro-apoptotic activity in some cell types, including retinal neurons.
Still, the use of receptor ligands believed to be involved in RGC apoptosis in glaucoma as therapeutics appears to be limited. The complex and often opposite functions associated with ligand binding to Trk and p75 receptors and the activation of multiple and pleiotrophic pathways makes in vivo NTF pharmacology difficult to predict. Indeed, clinical trials using recombinant NTF polypeptides to treat glaucoma have generally been disappointing. Further, recombinant proteins (e.g., NGF and other receptor ligands) for use in medical treatments tend to be difficult to manufacture and expensive to produce. What is needed is a treatment for glaucoma that halts RGC apoptosis and thus, disease progression due to continued vision (field) loss. A treatment that, unlike intraocular pressure normalizing drugs alone, targets the molecular mechanism underlying the death of RGCs and one that is specific enough to be effective.